Acute and chronic exposure of the skin to ultraviolet radiation (UVR) in natural sunlight induces damaging effects including sunburn, photo aging, photosensitivity and skin cancer. The damage to the skin caused by UVR is associated with the generation of highly reactive oxygen species (ROS) that oxidize critical components of the skin, leading to skin damage and disease. The aim of this proposed project is to synthesize a series of new antioxidant compounds that are designed for use as topical agents to protect the skin against UVR. These novel compounds are derived from naturally-occurring vitamin E (TOC, tocopherols) and vitamin E analogs (tocopheramines) and lipoic acid or lipoic acid derivatives (LA). The TOC and LA moieties are connected through a chemical link that is cleaved after the compounds are delivered to the viable epidermis, where the two active antioxidants are released. Both TOC and LA are potent antioxidants that are known to deactivate ROS and limit the subsequent damage caused by these compounds in the skin. In addition, TOC and LA interact directly or through endogenous ascorbic acid (ASC) to enhance and prolong their antioxidant effects when delivered to the skin in combination. The new compounds presented in this proposal overcome some of the limitations associated with previously prepared topical formulations of TOC, LA and combinations of these antioxidants. Specifically, our compounds are inherently more stable than formulations of TOC alone because the chemical connection between TOC and LA masks the susceptible phenolic group of TOC, which tends to be chemically unstable, especially in the presence of UVR. The carboxylic acid of LA is also masked in our compounds which eliminates the need for low pH formulations that are prone to causing skin irritation. Finally, these novel compounds allow for precise delivery and co-localization of the two antioxidants to the viable epidermis in a single formulation so that the synergistic activity between these compounds can be fully exploited. We aim to prepare up to 20 new compounds and to evaluate the penetration characteristics of these compounds into the viable epidermis using viable Micro-Yucatan pig skin as a model to mimic the compounds'behavior in human skin. We will also monitor the cleavage and release of the active antioxidants from these compounds in the epidermis and will assess the ability of the delivered compound to protect the skin against oxidative damage caused by exposure to UVR. The proposed project offers a unique training opportunity for both undergraduate and graduate students in the areas of drug synthesis, pharmaceutical formulation, topical drug delivery and assessment of drug efficacy. The multi-disciplinary approach described in the project is ideally suited to expose students to the drug development process and will serve to prepare students for positions in the pharmaceutical industry or to pursue advanced graduate training in medicinal chemistry or pharmaceutics. PUBLIC HEALTH RELEVANCE: Acute and chronic exposure of the skin to ultraviolet radiation (UVR) in natural sunlight induces damaging effects including sunburn,1 photoaging,2 immunosuppression3 and skin cancer.1, 4 Exposure of the skin to solar radiation, specifically UVA (315-400nm) and UVB (280- 315nm) radiation, has also been shown to deplete natural antioxidants that help to protect the skin against sun damage. The goal of this proposal is to prepare a series of new drugs for use as topical agents to protect the skin from UVR-induced damage. These agents are designed to replenish natural antioxidants in the skin for enhanced and extended photo protection relative to existing topical products. 1. MacKie, R.M. Effects of ultraviolet radiation on human health. Rad. Protect. Dos. 91 (1-3) 15-18, 2000. 2. Krutman, J. Ultraviolet A radiation-induced biological effects in human skin: relevance for photo aging and photodermatosis. J. Dermatol. Sci. 23 (Suppl1) S22-26, 2000. 3. Beissert, S.;Schwartz, T. Mechanisms involved in ultraviolet light-induce immunosuppression. J. Invest. Derm. Symp. Proc 4. 61-64, 1999. 4. Sarasin, A. The molecular pathways of ultraviolet-induced carcinogenesis. Mutat. Res. 428, 5-10, 1999. 5. Podda, M.;Traber, M.G. Weber, C.;Yan, L.J.;Packer, L. UV-radiation depletes antioxidants and causes oxidative damage in a model of human skin. Free Rad. Biol. Med. 24, 55-65, 1998.